3.1 Introduction to General Design Considerations
59
Low to moderate cytotoxicity was noted with these pyrazolyl thiazoles (Ivanenkov
et al. 2019a).
Other drugs as starting points
Drugs used for other disease treatments can also serve as templates for the eventual design of multi-action hybrids if they also show antibacterial activity alone
or in combination. Such drugs can be found by a number of approaches including
empirical screening or target based phenotypic screening or screening in wholeorganism models (Farha and Brown 2019). A number of drugs used for other purposes
have been identified with antibacterial activity as well (for example the anticystic
fibrosis drug ivacaftor) (as referenced in Kaul et al. 2019). Drugs that synergise
with antibacterials can also be identified through screening and such combinations would be of great interest to underpin novel hybrid designs. In related work,
two existing drugs were repurposed successfully in a dual combination, antitrypanosomal (Trypanosoma cruzi) treatment as discussed in the review by Oldfield
and Feng (2014). This review provides a good introduction to approaches to finding
multi-targeting inhibitors as antibacterials.
3.2 Designing for Mainly Dual Activity
3.2.1 Dual Action Antibacterial Hybrids
Research work on multi-action hybrid compounds to date has largely focused on the
design, synthesis and microbiological evaluation of dual action, or potentially dual
action, compounds. These compounds have been extensively reviewed (Domalaon
et al. 2018; Parkes and Yule 2016; Tevyashova et al. 2015; Shapiro 2013; Pokrovskaya
and Baasov 2010; Bremner et al. 2007) so only some selected examples are given here.
In general structural terms, many dual-mechanism or dual-action hybrids involve
two molecular recognition components separated by a linker unit which may be a
branched or unbranched chain or include the chain in ring systems. Omission of
a linker then leads to other possible hybrid structural templates namely where the
two molecular components containg the pharmacophores or target site recognition
elements are fused sharing a common bond or joined at a spiro centre, and chimeras
with partial to near full structural overlap. Note that the word ‘chimeric’ is derived
from the chimera in Greek mythology, a hybrid creature which, interestingly, is
usually depicted as a lion with the head of a goat arising from the body and with
the tail being a snake with a head at the end i.e. a tri-component hybrid. In biology
the term chimera refers to an organism whose cells arise from two or more zygotes
and it is in this general sense the word has been transposed to the hybrid chemical
structural framework.
With dual action hybrids, design is usually, though not always, based on results
from the combination of two antibacterials with two different recognition elements
59
Low to moderate cytotoxicity was noted with these pyrazolyl thiazoles (Ivanenkov
et al. 2019a).
Other drugs as starting points
Drugs used for other disease treatments can also serve as templates for the eventual design of multi-action hybrids if they also show antibacterial activity alone
or in combination. Such drugs can be found by a number of approaches including
empirical screening or target based phenotypic screening or screening in wholeorganism models (Farha and Brown 2019). A number of drugs used for other purposes
have been identified with antibacterial activity as well (for example the anticystic
fibrosis drug ivacaftor) (as referenced in Kaul et al. 2019). Drugs that synergise
with antibacterials can also be identified through screening and such combinations would be of great interest to underpin novel hybrid designs. In related work,
two existing drugs were repurposed successfully in a dual combination, antitrypanosomal (Trypanosoma cruzi) treatment as discussed in the review by Oldfield
and Feng (2014). This review provides a good introduction to approaches to finding
multi-targeting inhibitors as antibacterials.
3.2 Designing for Mainly Dual Activity
3.2.1 Dual Action Antibacterial Hybrids
Research work on multi-action hybrid compounds to date has largely focused on the
design, synthesis and microbiological evaluation of dual action, or potentially dual
action, compounds. These compounds have been extensively reviewed (Domalaon
et al. 2018; Parkes and Yule 2016; Tevyashova et al. 2015; Shapiro 2013; Pokrovskaya
and Baasov 2010; Bremner et al. 2007) so only some selected examples are given here.
In general structural terms, many dual-mechanism or dual-action hybrids involve
two molecular recognition components separated by a linker unit which may be a
branched or unbranched chain or include the chain in ring systems. Omission of
a linker then leads to other possible hybrid structural templates namely where the
two molecular components containg the pharmacophores or target site recognition
elements are fused sharing a common bond or joined at a spiro centre, and chimeras
with partial to near full structural overlap. Note that the word ‘chimeric’ is derived
from the chimera in Greek mythology, a hybrid creature which, interestingly, is
usually depicted as a lion with the head of a goat arising from the body and with
the tail being a snake with a head at the end i.e. a tri-component hybrid. In biology
the term chimera refers to an organism whose cells arise from two or more zygotes
and it is in this general sense the word has been transposed to the hybrid chemical
structural framework.
With dual action hybrids, design is usually, though not always, based on results
from the combination of two antibacterials with two different recognition elements